Oral drug delivery is the most widely utilized route of administration among all the routes that have been explored for systemic delivery of drugs via pharmaceutical products of different dosage form¹. Oral route is considered most natural, convenient and safe due to its ease of administration, patient acceptance, and cost effective manufacturing process. Pharmaceutical products designed for oral delivery are mainly immediate release type or conventional drug delivery systems, which are designed for immediate release of drug for rapid absorption^2,3.

Controlled release dosage form is a dosage form that release one or more drugs continuously in predetermined pattern for a fixed period of time, either systemically or locally to specified target organ^4,5. Greater attention is paid on development of oral controlled release drug delivery systems due to flexibility in designing of dosage form.

The main challenges to oral drug delivery systems are to deliver a drug at therapeutically effective rate to desirable site, modulation of GI transit time and minimization of first pass elimination. Control release dosage form provides better maintenance of optimal and effective drug level for prolonged duration with less dosing frequency and side effects^6,7.

Historically, oral drug administration has been the predominant route for drug delivery. It is known to be the most popular route of drug administration due to the fact the gastrointestinal physiology offers more flexibility in dosage form design than most other routes⁸. A major challenge for the pharmaceutical industry in drug development is to produce safe and efficient drugs, therefore properties of drugs and the way in which they are delivered must be optimized⁹.

A controlled release drug delivery system delivers the drug locally or systemically at a predetermined rate for a specified period of time. The goal of such systems is to provide desirable delivery profiles that can achieve therapeutic plasma levels. Drug release is dependent on polymer properties; thus, the application of these properties can produce well characterized and reproducible dosage forms¹⁰.

The basic rationale of a controlled release drug delivery system is to optimize the biopharmaceutics, pharmacokinetics, and pharmacodynamics properties of a drug in such a way that its utility is maximized through reduction in side effects and cure or control of disease condition in the shortest possible time by using smallest quantity of drug, administered by most suitable route^11,12. The immediate release drug delivery system lacks some features like dose maintenance, controlled release rate and site targeting. An ideal drug delivery system should deliver the drug at a rate dictated by the need of body over a specified period of treatment^13,14.

2. MATERIALS AND METHODS:

Oxybutynin was gifted from Sun Pharma Ltd, India. Karaya gum, Acacia and Tragacanth were procured from Research Lab Fine Chem Industries, India. Micro Crystalline Cellulose was procured from Shakti Chemicals, India. PVP K30 was procured from Merck Specialties Pvt. Ltd., India. Magnesium stearate and Talc were procured from S. D. Fine Chemicals Ltd., India.

Experimental Method:

Analytical method development:

a) Determination of absorption maxima:

100mg of Oxybutynin pure drug was dissolved in 100ml of Methanol (stock solution)10ml of above solution was taken and make up with100ml by using 0.1 N HCL (100μg/ml). From this 10ml was taken and make up with 100ml of 0.1 N HCL (10μg/ml). and pH 6.8 Phosphate buffer UV spectrums was taken using Double beam UV/VIS spectrophotometer. The solution was scanned in the range of 200 – 400nm.

b) Preparation calibration curve:

100mg of Oxybutynin pure drug was dissolved in 100ml of Methanol (stock solution) 10ml of above solution was taken and make up with 100ml by using 0.1 N HCL (100μg/ml). From this 10ml was taken and make up with 100ml of 0.1 N HCL (10μg/ml). The above solution was subsequently diluted with 0.1N HCL to obtain series of dilutions Containing 5,10,15,20 and 25μg/ml of Oxybutynin per ml of solution. The absorbance of the above dilutions was measured at 210nm by using UV-Spectrophotometer taking 0.1N HCL as blank. Then a graph was plotted by taking Concentration on X-Axis and Absorbance on Y-Axis which gives a straight line Linearity of standard curve was assessed from the square of correlation coefficient (R²) which determined by least-square linear regression analysis. The above procedure was repeated by using pH 6.8 phosphate buffer solutions.

Preformulation parameters:

The quality of tablet, once formulated by rule, is generally dictated by the quality of physicochemical properties of blends. There are many formulations and process variables involved in mixing and all these can affect the characteristics of blends produced. The various characteristics of blends tested as per Pharmacopoeia.

Angle of repose:

The frictional force in a loose powder can be measured by the angle of repose. It is defined as, the maximum angle possible between the surface of the pile of the powder and the horizontal plane. If more powder is added to the pile, it slides down the sides of the pile until the mutual friction of the particles producing a surface angle, is in equilibrium with the gravitational force. The fixed funnel method was employed to measure the angle of repose. A funnel was secured with its tip at a given height (h), above a graph paper that is placed on a flat horizontal surface. The blend was carefully pored through the funnel until the apex of the conical pile just touches the tip of the funnel. Angle of repose values were showed in Table 1. The radius (r) of the base of the conical pile was measured. The angle of repose was calculated using the following formula:

Tan θ = h / r

Tan θ = Angle of repose; h = Height of the cone; r = Radius of the cone base

Table 1: Angle of Repose values (as per USP)

Angle of Repose		Nature of Flow
<25		Excellent
25-30		Good
30-40		Passable
>40	Very poor

Bulk density:

Density is defined as weight per unit volume. Bulk density, is defined as the mass of the powder divided by the bulk volume and is expressed as gm/cm³. The bulk density of a powder primarily depends on particle size distribution, particle shape and the tendency of particles to adhere together. Bulk density is very important in the size of containers needed for handling, shipping, and storage of raw material and blend. It is also important in size blending equipment. 10 gm powder blend was sieved and introduced into a dry 20 ml cylinder, without compacting. The powder was carefully leveled without compacting and the unsettled apparent volume, Vo, was read.

The bulk density was calculated using the formula:

Bulk Density = M / V_o

Where, M = weight of sample

V_o = apparent volume of powder

Tapped density:

After carrying out the procedure as given in the measurement of bulk density the cylinder containing the sample was tapped using a suitable mechanical tapped density tester that provides 100 drops per minute and this was repeated until difference between succeeding measurement is less than 2 % and then tapped volume, V measured, to the nearest graduated unit. The tapped density was calculated, in gm per L, using the formula:

Tap = M / V

Where, Tap= Tapped Density; M = Weight of sample; V= Tapped volume of powder

Measures of powder compressibility:

The Compressibility Index (Carr’s Index) is a measure of the propensity of a powder to be compressed. It is determined from the bulk and tapped densities. In theory, the less compressible a material the more flowable it is. As such, it is measures of the relative importance of interparticulate interactions. In a free- flowing powder, such interactions are generally less significant, and the bulk and tapped densities will be closer in value.

For poorer flowing materials, there are frequently greater interparticle interactions, and a greater difference between the bulk and tapped densities will be observed. Carr’s index values were depicted in Table 2. These differences are reflected in the Compressibility Index which is calculated using the following formulas:

Carr’s Index = [(tap - b) / tap] × 100

Where, b = Bulk Density

Tap = Tapped Density

Table 2: Carr’s index values (as per USP)

Carr’s index	Properties
5 – 15	Excellent
12 – 16	Good
18 – 21	Fair to Passable
2 – 35	Poor
33 – 38	Very Poor
>40	Very Very Poor

Formulation development of Tablets:

All the formulations were prepared by direct compression. The compositions of different formulations are given in Table 3. The tablets were prepared as per the procedure given below and aim is to prolong the release of Oxybutynin. Total weight of the tablet was considered as 150 mg.

Preparation of Oxybutynin tablets:

Oxybutynin tablets were prepared by direct compression technique. Oxybutynin and all other ingredients were individually passed through sieve no ¹ 60. All the ingredients were mixed thoroughly by triturating up to 15 min. The powder mixture was lubricated with talc. The tablets were compressed using tablet compression machine (Lab Press Limited, India) by direct compression method.

Table 3: Formulation chart for tablets

Ingredients in mg	Formulation chart
Ingredients in mg	F1	F2	F3	F4	F5	F6	F7	F8	F9
Oxybutynin	5	5	5	5	5	5	5	5	5
Karaya gum	8	16	24	-	-	-	-	-	-
Acacia	-	-	-	8	16	24	-	-	-
Tragacanth	-	-	-	-	-	-	8	16	24
MCC	118	110	102	118	110	102	118	110	102
PVP K30	10	10	10	10	10	10	10	10	10
Magnesium stearate	4	4	4	4	4	4	4	4	4
Talc	5	5	5	5	5	5	5	5	5
Total weight (mg)	150	150	150	150	150	150	150	150	150

Evaluation of post compression parameters for prepared Tablets:

The designed formulation tablets were studied for their physicochemical properties like weight variation, hardness, thickness, friability and drug content.

Weight variation test:

To study the weight variation, twenty tablets were taken and their weight was determined individually and collectively on a digital weighing balance. The average weight of one tablet was determined from the collective weight. The weight variation test would be a satisfactory method of deter mining the drug content uniformity. Not more than two of the individual weights deviate from the average weight by more than the percentage shown in the following table and none deviate by more than twice the percentage. Pharmacopoeial specifications for tablet weight variation was depicted in Table 4. The mean and deviation were determined. The percent deviation was calculated using the following formula.

Individual weight – Average weight

% Deviation = -------------------------------------------× 100

Average weight

Table 4: Pharmacopoeial specifications for tablet weight variation

Average weight of tablet (mg) (I.P)	Average weight of tablet (mg) (U.S.P)	Maximum percentage difference allowed
Less than 80	Less than 130	10
80-250	130-324	7.5
More than	More than 324	5

Hardness:

Hardness of tablet is defined as the force applied across the diameter of the tablet in order to break the tablet. The resistance of the tablet to chipping, abrasion or breakage under condition of storage transformation and handling before usage depends on its hardness. For each formulation, the hardness of three tablets was determined using Monsanto hardness tester and the average is calculated and presented with deviation.

Thickness:

Tablet thickness is an important characteristic in reproducing appearance. Tablet thickness is an important characteristic in reproducing appearance. Average thickness for core and coated tablets is calculated and presented with deviation.

Friability:

It is measured of mechanical strength of tablets. Roche friabilator was used to determine the friability by following procedure. Pre weighed tablets were placed in the friabilator. The tablets were rotated at 25rpm for 4 minutes (100 rotations). At the end of test, the tablets were re weighed, loss in the weight of tablet is the measure of friability and is expressed in percentage as

% Friability = [(W1-W2) / W] × 100

Where,

W1 = Initial weight of three tablets

W2 = Weight of the three tablets after testing

Determination of drug content:

Tablets were tested for their drug content. Ten tablets were finely powdered quantities of the powder equivalent to one tablet weight of drug were accurately weighed, transferred to a 100ml volumetric flask containing 50ml water and were allowed to stand to ensure complete solubility of the drug. The mixture was made up to volume with media. The solution was suitably diluted and the absorption was determined by UV –Visible spectrophotometer. The drug concentration was calculated from the calibration curve.

In vitro drug release studies:

900ml 0f 0.1 HCL was placed in vessel and the USP apparatus –II (Paddle Method) was assembled. The medium was allowed to equilibrate to temp of 37°c + 0.5°c. Tablet was placed in the vessel and apparatus was operated for 2 hours and then the media 0.1 N HCL was removed and pH 6.8 phosphate buffer was added process was continued from upto 12 hrs at 50 rpm. At definite time intervals withdrawn 5 ml of sample, filtered and again 5ml media was replaced. Suitable dilutions were done with media and analyzed by spectrophotometrically at 210 and 215 nm using UV-spectrophotometer.

Drug – Excipient compatibility studies:

Fourier Transform Infrared (FTIR) spectroscopy:

The compatibility between the pure drug and excipients was detected by FTIR spectra obtained on Bruker FTIR Germany (Alpha T). The solid powder sample directly place on yellow crystal which was made up of ZnSe. The spectra were recorded over the wave number of 4000 cm^-1 to 400 cm^-1.

3. RESUTS AND DISCUSSION:

The present study was aimed to developing Controlled release tablets of Oxybutynin using various polymers. All the formulations were evaluated for physicochemical properties and in vitro drug release studies.

Analytical Method:

Graphs of Oxybutynin was taken in Simulated Gastric fluid (pH 1.2) and in p H 6.8 phosphate buffer at 210 nm and 215 nm respectively. It was found that the estimation of Oxybutynin by UV spectrophotometric method at λ_max210 nm in 0.1N Hydrochloric acid had good reproducibility and this method was used in the study. Standard graph of Oxybutynin in 0.1N HCl was depicted in Figure 1. The correlation coefficient for the standard curve was found to be closer to 1, at the concentration range, 5-25μg/ml. The regression equation generated was y = 0.023x+0.003.

Figure 1: Standard graph of Oxybutynin in 0.1N HCl

It was found that the estimation of Oxybutynin by UV spectrophotometric method at λ_max215 nm in pH 6.8 Phosphate buffer. had good reproducibility and this method was used in the study. Standard graph of Oxybutynin pH 6.8 phosphate buffer (215nm) was depicted in Figure 2. The correlation coefficient for the standard curve was found to be closer to 1, at the concentration range, 5-25μg/ml. The regression equation generated was y = 0.027x + 0.008.

Table 5: Pre-formulation parameters of Core blend

Formulations	Bulk Density (gm/cm²)	Tap Density (gm/cm²)	Carr’s Index (%)	Hausner ratio	Angle of Repose(Ɵ)
F₁	0.45	0.55	18.1	1.22	26.2
F₂	0.47	0.55	14.5	1.17	25.4
F₃	0.50	0.58	13.7	1.16	26.8
F₄	0.46	0.55	16.3	1.19	24.8
F₅	0.50	0.58	13.7	1.16	24.3
F₆	0.47	0.55	14.5	1.17	26.3
F₇	0.50	0.58	13.7	1.16	26.4
F₈	0.41	0.50	18.6	1.21	24.3
F₉	0.41	0.50	18.8	1.21	28.4

Table 6: In vitro quality control parameters for tablets

Formulation code	Average Weight (mg)	Hardness(kg/cm²)	Friability (%)	Thickness (mm)	Drug content (%)
F1	149.25	5.4	0.62	3.58	97.12
F2	147.10	5.9	0.48	3.25	99.81
F3	148.37	4.8	0.32	3.47	97.36
F4	149.65	5.7	0.49	3.16	99.32
F5	145.82	4.3	0.61	3.82	98.57
F6	150.2	5.8	0.25	3.65	96.87
F7	148.79	4.5	0.37	3.73	99.20
F8	149.28	4.6	0.18	3.19	97.56
F9	149.57	5.2	0.46	3.22	99.60

All the parameters such as weight variation, friability, hardness, thickness and drug content were found to be within limits.

From the results, it was observed that, formulation F4 (98.14%) showed fastest drug release by the end of 20th h. Formulation F1, F2, F3, F5, F6, F7, F8 and F9 showed the release upto 66.80%, 73.43%, 86.51%, 90.67%, 85.23%, 86.14%, 96.54% and 90.23% respectively at the end of 12 h.

Figure 3: In vitro drug release for prepared formulations (F1-F9)

From the dissolution data it was evident that the formulations prepared with Karaya gum polymer (high concentrations) were able to retard the drug release up to desired time period i.e., 12 hours. The Formulation Containing Acacia in 8 mg Concentration Showed good retarding nature with required drug release in 12 hours i.e., 98.14 %. Whereas the formulations prepared with Tragacanth were retarded the drug release in the concentration of 16 mg (F8 Formulation) showed required release pattern i.e., retarded the drug release up to 12 hours and showed maximum of 96.54 % in 12 hours with good retardation. From the above results it was evident that the formulation F4 is best formulation with desired drug release pattern extended up to 12 hours.

Compatibility Study by FT-IR:

Chemical interaction between Oxybutynin and with various combinations of polymers, excipients and optimized formulation was studied by using FTIR. It was obtained from the results, that there was no change in shift of characteristic peaks, hence it conforms that the prepared optimized formulation was compatible to the pure drug. The interpretation of IR spectra of optimized formulation (F4) was showed in Table 7 and FTIR Spectrum of pure drug and optimized formulation (F4) was depicted in Figure 4.

Table 7: Interpretation of IR spectra of formulation F4

Characteristic peak	Frequency range (cm ^-1 )	Observed frequency (cm^-1)
O-H	3200-3600	3342.35
C=C	1400-1600	1514.32
C=C	2900-3100	2911.23
C-N	1020-1220	1136.68

CONCLUSION:

The present investigation was carried out for controlling the drug release up to 12 hrs. For controlling the drug release polymers used such as Karaya gum, Acacia and Tragacanth. From the investigation studies were found that the standard graph was given that regression analysis R² value was 0.999 in 0.1 N HCl and 0.998 in pH 6.8 phosphate buffer. FTIR results were shown good compatibility between drug and excipients. All the pre and post compression studies such as Bulk density, tapped density, angle of repose, Carr’s index, Hausner’s ratio, Weight variation, Thickness, Hardness, Drug content were found to be within limits. In vitro drug release studies revealed that among all formulations F4 formulation was considered as optimized formulation which contain Acacia as polymer in the concentration of 8 mg. Drug release kinetic studies were done for optimized formulation. It was followed Zero order release kinetics.

REFERENCES:

1. Sathish U, Shravani B, Raghavendra Rao NG, Srikanth Reddy M, Sanjeev NB. Overview on controlled release dosage form. Int J Pharm Sci. 2013;3(4):258-269.

2. Ali N, Shaista R, Pryia P, Kofi A. The Role of oral controlled release matrix tablets in drug delivery systems. Bioimpacts. 2012;2(4):175–187.

3. Mamidala R, Ramana V, Lingam M, Gannu R, Rao MY. Review article factors influencing the design and performance of oral sustained/controlled release dosage form. Int. J. Pharm. Sci. Nanotech. 2009;2:583.

4. Patel N, Chaudhary A, Soni T, Sambyal M, Jain H, Upadhyay U. Controlled drug delivery system: A Review. Indo American J Pharm Sci. 2016;3 (3):227-233.

5. Kumar S, Shashikant, Bharat P. Sustained release drug delivery system: A Review. Int. J. Inst. Pharm. Life Sci. 2012;2(3):356-376.

6. Kar RK, Mohapatra S, Barik BB. Design and characterization of controlled release matrix tablets of Zidovudine. Asian J Pharm Cli Res. 2009;2:54.

7. Cristina M, Aranzaz Z, Jose ML. Critical factors in the release of drugs from sustained release hydrophilic matrices. J Control Rel. 2011;154:2-19.

8. Chugh I, Seth N, Rana AC and Gupta S. Oral sustained release drug delivery system: an overview. Int Res J Pharm. 2012;3(5):57-62.

9. Bhargava A, Rathore RPS, Tanwar YS, Gupta S, Bhaduka G. Oral sustained release dosage form: an opportunity to prolong the release of drug. Int J Adv Res Pharm Bio Sci. 2013;3(1):7-14.

10. Thakor RS, Majmudar FD, Patel JK, Rajpit JC. Review: Osmotic drug delivery systems current scenario. J Pharm Res. 2010;3(4):771- 775.

11. Modi K, Modi M, Mishra D, Panchal M, Sorathiya U, Shelat P. Oral controlled release drug delivery system: an overview. Int Res J Pharm. 2013;4(3):70-76.

12. Ratnaparkhi MP, Gupta JP. Sustained release oral drug delivery system - an overview. Int J Pharm Res Rev, 2013;2(3):11-21.

13. Shah N, Patel N, Patel KR, Patel D. A review on osmotically controlled oral drug delivery systems. J Pharm Sci Bio Res. 2012;2(5):230-237.

14. Thombre NA, Aher AS, Wadkar AV, Kshirsagar SJ. A review on sustained release oral drug delivery system. Int J Pharm Res Sch, 2015;4(2):361-371.

15. Dusane AR, Gaikwad PD, Bankar VH, Pawar SP. A review on: sustained released technology. Int J Res Ayu Pharm. 2011;2(6):1701-1708.

16. Shamma SP, Haranath C, Reddy CPS, Sowmya C. An overview on SR tablet and its technology. Int J Pharm Drug Ana. 2014;2(9):740-747.

17. Tulshi C, Natasha, Vipin S, Rubi. Formulation and Evaluation of Controlled Release Floating Tablets Of Cefixime Using Hydrophilic Polymers. Int. Res. J. Pharm. 2019,10(1).

18. Ram Prasad B, Bhikshapathi DVRN. Design and in vivo Evaluation of Controlled Release Gliclazide Trilayer Matrix Tablets in the Management of Diabetes Mellitus. Int J Pharm Sci Drug Res. 2018;10(5):410-417.

19. Meena S, Manivannan R, Santhosh KG. Formulation and Evaluation of Telmisartan with Hydrochlorothiazide Conventional Release Tablets. Int J Pharm Pharm Res. 2018;12(4):50-59.

Received on 06.10.2019 Modified on 04.12.2019

Research J. Pharm. and Tech. 2020; 13(8):3854-3860.

DOI: 10.5958/0974-360X.2020.00682.4